DESCRIPTION: ApoE3 has been shown to promote neurite outgrowth when provided to neuronal cells in the presence of lipid. Histochemical evidence suggests that apoE3 also accumulates in the cytoplasm of neuronal cells and it associates in vitro with specific microtubule associated proteins. ApoE4, a less prevalent isoform of apoE, does not share these properties of apoE3. This suggests that apoE3 has a intracellular role in normal neuronal development that is not shared by apoE4. This may account in part for the fact that apoE4 is a genetic risk factor for the development of Alzheimer's disease. The goal of this proposal is to examine the influence of apoE4 on neurite outgrowth using GT1-1 trk-9 cells exposed to exogenous apoE or stably expressing apoE in the cells. Specifically, the applicant will examine whether and by what mechanism apoE gains access to the cytoplasm, whether specific intracellular targeting of apoE3 can also influence these processes, and the role of LRP in delivering apoE and lipid to the appropriate intracellular compartment. Finally the applicant will determine whether neurite outgrown, apoE stability, and microtubule stability are tightly coupled by determining whether the same domains of apoE3 influence these three processes. These results should provide important information about the physiological role of apoE in neuronal growth and differentiation.